title: Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.
abstract: 5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.).
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: goto.taiji.kt@daiichisankyo.co.jp.
authors.forename: Taiji
authors.initials: T
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Shiina
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizukami
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hirahara
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakao
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C030986:pyrimidine
keywords: 2-Phenylpyrimidine; COPD; Crystallography; PDE4; PDE4 inhibitor; PDE4B; cAMP